The renin angiotensin system (RAS) exerts many diverse physiological functions throughout the body, mediated by its effector peptide, angiotensin II (AngII). AngII has been linked with a variety of different functions ranging from the initiation of severe vascular pathologies, such as atherosclerosis and abdominal aortic aneurysm (AAA), to mundane physiological processes of fluid homeostasis, vascular contraction, and regulation of blood pressure. To provide a potential link between these functions, an in-depth analysis of regional effects of AngII on aortic vasculature was performed. The studies presented in this dissertation tested the overall hypothesis of whether regional changes exist in the vasculature in response to angiotensin II (AngII). We first infused AngII into C57BL/6 animals and studied the aortic morphology in detail. On first glance, we detected a thickening throughout the aorta, with no overt changes from region to region. However, upon further analysis, it was demonstrated that there was a region-specific aortic arch hyperplasia, versus the hypertrophy in the remainder of the aorta. Through a series of experiments, this hyperplasia was linked to the redox-mediated protein Id3. Further analysis of the vasculature demonstrated AngII exerted aortic contractions which were limited to the infrarenal aorta. These contractions were mediated by the AT1b receptor subtype in the RAS. We also demonstrate that AngII leads to suprarenal specific formation of AAA, which can be attenuated by the deletion of specific innate immune mediator proteins, such as MyD88 and TLR4. Overall, these data suggest many region-specific roles for AngII in the aortic vasculature and provide many novel findings as to the cause of these effects.

Aryl Hydrocarbon Receptor (AhR) is a ligand-actviated receptor known as the dioxin receptor. Environmental pollutants called dioxin-like toxicants are found in food, cigarette smoke, automobile exhaust and air. Therefore, they could chronically amplify the pathology of numerous chronic inflammatory diseases. AhR is a well known target of these environmental chemicals that disrupt endocrine signaling. By the year 2020, the number of people older than 60 years is expected to top 1 billion. The burden of treating chronic disease is significant both in dollars spent and in lost productivity. The need to identify risk factors for chronic diseases must be evaluated along with diet and lifestyle factors that will promote healthy aging. The studies presented in this dissertation tested the hypothesis that habitual exposure to dioxin-like contaminants contributes to chronic inflammatory disease states through activation of AhR pathway. Due to their lipophilicity, dioxin like toxicants (like PCB 77) accumulated in mice' visceral adipose tissue and induced adipocytes maturation and ectopic fat deposition. Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCB 77) can cause endothelial cells activation and inflammation by inducing pro-inflammatory signaling pathways. In our studies, PCB 77 had cumulative effects in Angiotensin II - induced Abdominal Aortic Aneurysm (AAA) by exacerbating inflammation in and around the aortic wall. More, PCB 77 increased mortality in mice that developed AAA. In order to appreciate the AhR involvement in inflammation we used a mouse model of Inflammatory Bowel Disease(IBD). Mice that had a reduced Ahr Receptor expression developed a less severe colitis and had a decreased general inflammatory status. These data provide evidence that exposure to environmental toxicants could augment inflammation and contribute to the social burden of obesity and obesity related chronic inflammatory diseases.

L’athérosclérose et la pathologie anévrysmale sont principalement caractérisées par un remodelage de laparoi artérielle au cours de leur évolution. Ce travail a examiné un aspect de la destruction de la paroiartérielle à travers l’étude de la métalloprotéase MMP-14 au cours de l’athérome et un aspect dereconstruction artérielle à travers l’étude d’une thérapie cellulaire d’un modèle d’Anévrysme de l’AorteAbdominale (AAA) par Cellules Souches Mésenchymateuses (CSMs).En utilisant un modèle de greffe de Moëlle Osseuse (MO) dans des souris Ldlr-/-, nous avons montré que ladélétion d’expression de MMP-14 dans les cellules issues de la MO provoquait une accumulation decollagène interstitiel dans la plaque athéromateuse sans modification de la composition cellulaire nivariation de taille. Une mesure de l’activité collagénolytique par substrat fluorescent a confirmé que ladélétion en MMP-14 chez les macrophages provoquait une baisse de l’activité collagénolytique. Cetteactivité est indépendante de l’activité MMP-2 et MMP-8 et pourrait être médiée partiellement parl’activation de MMP-13. Nous avons mis en évidence la présence de CSMs à la surface luminale de thrombus de AAA et nous avonsmontré une diminution significative des CSMs circulantes chez des patients porteurs de AAA. Nous avonspu stabiliser la croissance de AAA expérimentaux chez le rat à partir de xénogreffe artérielle par perfusionendoluminale de CSMs. La perfusion de CSMs provoquait une diminution de l’inflammation à court termeet favorisait la reconstruction artérielle par accumulation de collagène et d’élastine à moyen terme.En conclusion, l’activité collagénolytique de MMP-14 est un des mécanismes moléculaires possibles del’évolution de la plaque athéromateuse par rupture de plaque. Elle ouvre la perspective d’une nouvelleapproche thérapeutique et pourrait être une cible comme substrat pour une imagerie fonctionnelle de laplaque athéromateuse. L’évolution de la maladie anévrysmale pourrait être secondaire à une altération dessystèmes de réparation tissulaire dont les CSMs seraient des acteurs clé. La perfusion endoluminale desCSMs dans un modèle expérimental a permis la restauration de ces systèmes de réparation tissulaire etouvre la perspective d’un nouvel outil thérapeutique contre les AAA / Pas de résumé anglais

Abdominal aortic aneurysm (AAA) is a form of cardiovascular disease whereby a change in the material properties of the vessel wall results in a localised dilation of the abdominal aorta. The primary risk of AAAs is rupture with mortality rates close to 90%. Whilst surgical intervention can be performed to repair AAAs, such procedures are considered high risk. As a result, surgery is only performed upon AAAs that are considered likely to rupture. The current method of prediction is the diameter criterion, with surgical intervention performed if the diameter of the AAA exceeds 5.5cm. Research has demonstrated that this is a weak method of predicting rupture and as such other methodologies are sought. One promising method is patient specific modelling (PSM) which involves the reconstruction of individual patient AAA geometries from imaging datasets, and finite element analysis (FEA) to calculate the stresses acting on the AAA wall, with the peak stress typically used as the predictor. A weakness of this methodology is the lack of patient specific material property values defined in the simulation. A potential technique to address this limitation is magnetic resonance elastography (MRE), an MR-based technique which utilises a phase-contrast sequence to characterise displacements caused by shear waves induced into the tissue by an external mechanical driver. An inversion algorithm is used to calculate local material property values of the tissue from these displacements. The aim of this thesis was to investigate the capability of utilising MRE to obtain material property measurements from AAAs that could be incorporated into PSM. To achieve this an FE method of modelling MRE was developed. The influence of modelling parameters upon the material property measurements made using the direct inversion (DI) algorithm was investigated, with element type and boundary conditions shown to have an effect. The modelling technique was then utilised to demonstrate the influence that the size of an insert had upon shear modulus measurements of that insert using DI in both 2- and 3-dimensions, and the multi-frequency dual elasto-visco algorithm (MDEV), an extension of DI combining information from multiple frequencies. Meanwhile a comparison of the modelling technique against an MRE scan of a phantom showed that whilst measurements made from the two techniques were different at low frequencies, they became similar as the frequency increased. This suggested that such differences were attributable to increased noise in the scanned data. FEA of MRE performed on idealised AAA geometries demonstrated that AAA size, shear viscosity of the thrombus and shear modulus of the AAA wall all influenced the accuracy of MRE measurements in the thrombus. Meanwhile MRE scanning of a small cohort of AAA patients had been undertaken and phase images investigated for signs of wave propagation to investigate the capabilities of the current MRE setup. Phase images were dominated by noise and there was no wave propagation visualised in any of the AAAs. This thesis demonstrates that the current MRE setup is not capable of achieving accurate measurements of material properties of AAA for PSM. Visualisation of wave propagation in AAAs is technically demanding and requires further development. A more fundamental concern however is the size dependence of the inversion algorithm used and the inability to consistently make accurate measurements from AAA geometries.

Introduction: Abdominal aortic aneurysms (AAA) have a prevalence of approximately 2%, and are more common in men. AAAs are generally asymptomatic, but if ruptured and untreated, the mortality rate is close to 100%. Screening programs for AAAs are implemented in Sweden, the UK, and the US. This study describes the different views of AAA screening with a special emphasis on underlying ethical issues. Aim: To analyze the scientific background of AAA screening in order to be able to discuss its ethical basis. Methods: This was a qualitative literature study with an analysis of arguments using a hermeneutic method. Articles were obtained through a literature search and consisted of official articles, scientific articles, and debate articles. Results: A recent dissertation has questioned the value of AAA screening because of decreased AAA mortality and risk for overdiagnosis. However, most studies and official recommendations are in favor of AAA screening because disease specific mortality decreases and the screening program is considered cost-effective. Conclusion: This study shows that intellectual passion has created an unusually polarized discussion. It seems that benefit outweighs harm. Since AAA screening is the first screening program which could lead to the death of a previously asymptomatic individual, well founded informed consent is extremely important. Finally, both decisions to act and not to act have moral consequences.

Abdominal aortic aneurysms (AAAs), a permanent dilation in the abdominal region of the aorta, is a highly sexually dimorphic disease. AAAs prevalence is ranging from 4-10 fold higher in males than females. Defining the mechanistic basis for reduced (in females) or increased (in males) AAA formation and progression may uncover potential therapeutic targets. The majority of studies examining sexual dimorphism focus on the role of sex hormones. However, genes residing on sex chromosomes, in addition to sex hormones, may contribute to sexual dimorphism of AAAs. For example, the X chromosome contains about 5% of the whole genome, but the role of sex chromosomes genes to sexual dimorphism of cardiovascular diseases such as AAAs is largely unknown. The purpose of this study was to determine the role of sex chromosomes as mediators of sex differences for angiotensin II (AngII)-induced AAAs in hypercholesterolemic mice. We used the four core genotype murine model, which enables the creation of phenotypically normal male and female mice with an XX versus XY sex chromosome complement, to test the hypothesis that an XY sex chromosome complement promotes AngII-induced AAAs. Transgenic male mice expressing the Sry gene on an autosome, but not on the Y-chromosome, were bred to female low-density lipoprotein receptor deficient mice to create male and female mice with an XX or an XY sex chromosome complement. In females, an XY sex chromosome complement doubled the incidence and markedly increased the severity of AngII-induced AAAs. To define mechanisms, we examined gene expression patterns in abdominal aortas and demonstrated elevated expression of inflammatory genes that were linked to increased MMP activity and oxidative stress in aortas from XY females. Moreover, administration of testosterone to XY females, to mimic males, resulted in a striking level of aneurysm rupture. In males, transcriptional profiling of abdominal aortas revealed 450 genes that were influenced by sex chromosomes. Infusion of AngII to XY males resulted in diffuse pathology along the length of the aorta, while XX males developed focal AAAs, with pathology reduced by orchiectomy in both genotypes. Thoracic aortas of XY males exhibited adventitial thickening which was not exist in thoracic aortas from XX males. Following a prolonged period (3 months) of AngII infusions XY males had AAAs with expanded aortic walls, while XX males had thin walled dilated AAAs. In summary, our findings demonstrate a remarkable effect of sex chromosome complement to regulate aortic vasculature and disease development. Aside from demonstrating mechanisms of sexual dimorphism of aortic diseases, these findings indicate that chronic sex hormone therapy in the aging and transgender population may have cardiovascular ramifications. Moreover, identification of targets influenced by sex chromosomes and/or sex hormones in a manner that predicts disease development may identify sex-specific approaches to cardiovascular therapy.

Objective: To assess neck angulation and endograft oversizing as factors contributing to folding. Endograft folding will then be assessed on its role in endograft fixation strength. Methods: Bench top flow loop experiments were performed with barbless Gore Excluder endovascular grafts (EVG) that were deployed into silicone aorta-AAA models with neck angles of 0, 30, and 60. A total of five oversizings were tested: -7%, 2%, 12%, 24%, and 38% with N= 3 for each oversizing at each neck angle for a total of 45 experiments. Photographs of the stent apex to apex distances were taken for the entire circumference of the device for a total of 8 photos per experiment. Measurements of the apex to apex distance were taken for the top three stent layers and variance for each stent layer was calculated. Variances for all three stent layers were summed to represent the folding metric. The silicone model was then removed from the flow loop and placed on the uniaxial extension tester to for pull out testing to assess impact on attachment strength. Results: Neck angle and oversizing increases folding risk at oversizing ≥12% for 0° and 30° neck angles, and ≥ 2% oversizing for a 60° neck angle. Folding metric comparison between 0° vs. 30° and 0° vs. 60° across all oversizings had statistical significance (Mann-Whitney U, p

Rupture of abdominal aortic aneurysm (AAA) is a catastrophic event that leads to high mortality and morbidity in patients. The primary causes associated with aneurysm rupture remain poorly understood despite rigorous investigations. Reports have shown that AAA that went on to rupture or present ruptured had higher peak wall tension (stress resultant) than those that did not go on to rupture or present ruptured. Studies investigating the material strength of ruptured AAA and unruptured AAA revealed that the uniaxial failure strength in ruptured AAA is no different on average than unruptured AAA. However, it is poorly understood whether uniaxial failure properties are reliable as they are not indicative of the manner in which failure occurs in biological soft tissues. Multi-axial failure properties using a bubble inflation test (BIT) have been implemented by various groups but have not been directly compared against uniaxial failure properties. The current study seeks to develop a BIT apparatus, to compare multi-axial and uniaxial failure properties of fibrous anisotropic biological soft tissues (bovine aorta) and non-fibrous isotropic molded silicon, and to perform a survey of computational indices at the rupture sites of four ruptured AAA. Two versions of the BIT apparatus were developed: a manual that was developed allows for a large amount of failure properties to be extracted that can identify localized weaknesses. It was found that circumferentially oriented multi-axial failure was correlated with longitudinally oriented uniaxial failure properties, however, for oblique oriented multi-axial failure the correlation decreased. Utilizing the insights gained from the multi-axial experiments it was determined that the failure properties used in the computational study with the data from Raghavan et al. were appropriate for use in retrospective assessment of the rupture site in four ruptured AAA computational models. Although the study was inconclusive in finding causation, the rupture line of each aneurysm had indices ranging between the third quartile and peak values for tension to failure tension ratio, nodal displacement magnitude, strain energy per unit volume and strain energy per unit surface area. This study provides a framework for interrogating failure properties at a higher density of measurement and a heterogeneous computational model that has the potential to predict AAA rupture in the future.

Abdominal aortic aneurysm (AAA) is a common disease that develops gradually over several years and is characterised by weakening and dilatation of the aortic wall. AAAs also demonstrates a marked inflammatory infiltrate throughout the aortic wall. Chlamydophila pneumoniae (C. pneumoniae), is a common bacterium. About 50% of the population has been infected in adolescence. Thirteen studies report the presence of either C. pneumoniae or its antigens in 35-100% of AAA specimens. The overall aim of this thesis was to evaluate the possible role of C. pneumoniae in inflammatory response and expansion of AAA from a clinical point of view. In paper I, viable C. pneumoniae was detected in a majority of 26 patients with AAA having open surgery. Patients operated for AAA had higher C. pneumoniae antibodies titers than controls. In paper II, 247 patients were randomised in a double-blind trial, to evaluate the effect of azithromycin on the expansion of small AAAs. No such effect was seen and there was no correlation between C. pneumoniae antibody titers and AAA expansion. In paper III, 42 patients with AAA were compared to 100 age- and sex matched controls with normal aortas. C. pneumoniae antibodies were analysed in plasma samples obtained at screening, and in samples from a study conducted 5-15 (mean 12) years previously on the same population. There was no significant difference between the groups. In paper IV, were 211 patients were analysed, we could not find an association between levels in plasma of three markers of inflammation (IL-6, MMP-9 and CRP) and AAA expansion. A significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins. In conclusion, viable C. pneumoniae is found at the scene of the crime, but we were unable to reverse or halt expansion of AAA with antibiotic treatment. C. pneumoniae antibody titers cannot be used, to detect small AAA, or to evaluate AAA expansion. From a clinical point of view, based on the methods and analyses used in this thesis, the role of C. pneumoniae in the inflammatory response and expansion of abdominal aortic aneurysms is limited.

Abdominal aortic aneurysm (AAA) is a common disease that is life threatening when rupture occurs. The aims of this thesis were to study (I) the long-term survival after AAA repair, (II) the cost of repair with open (OR) and endovascular (EVAR) technique, (III) the effect of different statistical methods on interpretation of cost data, (IV) the prevalence of the disease among patients with suspected arterial disease referred to the vascular laboratory, and (V) the cost-effectiveness of selective high-risk screening. Analyses of data from the Swedish vascular registry (Swedvasc), local patient registries, patient records and hospital cost registries form the basis of this thesis. Short- and long-term survival after intact AAA repair improved over the past two decades, despite increasing patient age and rate of comorbidities over time. Compared to a general population adjusted for age, sex and calendar year, the relative 5-year survival was 90% among those surviving repair. While short-term survival improved over time after ruptured repair, relative long-term survival was stable. Despite differences in patient selection and cost structure, the total cost of AAA repair with EVAR and OR was similar in a population based setting (€28,193). There was lack of consistency in the methods used in cost-analysis in the current literature, and p-values were highly dependent on test method. The practice of selective (non-population-based) screening for AAA among patients referred to the vascular laboratory was studied. The prevalence of AAA was 4.2% among male and 1.5% among female patients. AAA was associated with high age and prevalence of arterial stenosis. Of AAAs detected through selective screening, 21.5% had undergone elective repair at 7.5 years follow-up. In a health-economic evaluation, the incremental cost-effectiveness ratio of selective screening was €11,084 per life year gained. In conclusion, survival after intact AAA repair has improved over time, despite changes in case-mix. Results of health economic reports on cost of AAA repair can be highly dependent on patient selection as well as presentation of data and the statistical methods used. Selective screening for AAA among patients referred to the vascular laboratory is cost-effective.